SYSTEMATIC REVIEW

published: 03 May 2022

doi: 10.3389/fcvm.2022.849201

Edited by:

Maria Lucia Narducci,

Catholic University of the Sacred

Heart Rome, Italy

Reviewed by:

Giannis G. Baltogiannis,

Vrije University Brussel, Belgium

Josef Kautzner,

Institute for Clinical and Experimental

Medicine (IKEM), Czechia

Marek Sramo,

Institute for Clinical and Experimental

Medicine (IKEM), Czechia

*Correspondence:

Stefania Volpe

stefania.volpe@ieo.it

orcid.org/0000-0003-0498-2964

These authors share last authorship

Specialty section:

This article was submitted to

Cardiac Rhythmology,

a section of the journal

Frontiers in Cardiovascular Medicine

Received: 05 January 2022

Accepted: 22 March 2022

Published: 03 May 2022

Citation:

Franzetti J, Volpe S, Catto V,

Conte E, Piccolo C, Pepa M,

Piperno G, Camarda AM, Cattani F,

Andreini D, Tondo C,

Jereczek-Fossa BA and

Carbucicchio C (2022) Stereotactic

Radiotherapy Ablation and Atrial

Fibrillation: Technical Issues

and Clinical Expectations Derived

From a Systematic Review.

Front. Cardiovasc. Med. 9:849201.

doi: 10.3389/fcvm.2022.849201

Stereotactic Radiotherapy Ablation

and Atrial Fibrillation: Technical

Issues and Clinical Expectations

Derived From a Systematic Review

Jessica Franzetti1,2, Stefania Volpe1,2*, Valentina Catto3,4, Edoardo Conte5,

Consiglia Piccolo6, Matteo Pepa1, Gaia Piperno1, Anna Maria Camarda1,2,

Federica Cattani6, Daniele Andreini5,7, Claudio Tondo3,8,

Barbara Alicja Jereczek-Fossa1,2 and Corrado Carbucicchio3

1 Department of Radiation Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy, 2 Department of Oncology

and Hemato-Oncology, University of Milan, Milan, Italy, 3 Department of Clinical Electrophysiology and Cardiac Pacing,

Centro Cardiologico Monzino IRCCS, Milan, Italy, 4 Department of Electronics, Information and Biomedical Engineering,

Politecnico di Milano, Milan, Italy, 5 Cardiovascular Computed Tomography and Radiology Unit, Centro Cardiologico

Monzino IRCCS, Milan, Italy, 6 Unit of Medical Physics, European Institute of Oncology (IEO) IRCCS, Milan, Italy,

7 Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Milan, Italy, 8 Department of Biomedical,

Surgical and Dental Sciences, University of Milan, Milan, Italy

Aim: The purpose of this study is to collect available evidence on the feasibility

and efficacy of stereotactic arrhythmia radio ablation (STAR), including both photon

radiotherapy (XRT) and particle beam therapy (PBT), in the treatment of atrial fibrillation

(AF), and to provide cardiologists and radiation oncologists with a practical overview on

this topic.

Methods: Three hundred and thirty-five articles were identified up to November 2021

according to preferred reporting items for systematic reviews and meta-analyses criteria;

preclinical and clinical studies were included without data restrictions or language

limitations. Selected works were analyzed for comparing target selection, treatment plan

details, and the accelerator employed, addressing workup modalities, acute and long-

term side-effects, and efficacy, defined either by the presence of scar or by the absence

of AF recurrence.

Results: Twenty-one works published between 2010 and 2021 were included.

Seventeen studies concerned XRT, three PBT, and one involved both. Nine studies

(1 in silico and 8 in vivo; doses ranging from 15 to 40 Gy) comprised a total of 59

animals, 12 (8 in silico, 4 in vivo; doses ranging from 16 to 50 Gy) focused on humans,

with 9 patients undergoing STAR: average follow-up duration was 5 and 6 months,

respectively. Data analysis supported efficacy of the treatment in the preclinical setting,

whereas in the context of clinical studies the main favorable finding consisted in the

detection of electrical scar in 4/4 patients undergoing specific evaluation; the minimum

dose for efficacy was 25 Gy in both humans and animals. No acute complication was

recorded; severe side-effects related to the long-term were observed only for very

high STAR doses in 2 animals. Significant variability was evidenced among studies in

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Franzetti et al.

Stereotactic Ablation for Atrial Fibrillation

the definition of target volume and doses, and in the management of respiratory and

cardiac target motion.

Conclusion: STAR is an innovative non-invasive procedure already applied for

experimental treatment of ventricular arrhythmias. Particular attention must be paid

to safety, rather than efficacy of STAR, given the benign nature of AF. Uncertainties

persist, mainly regarding the definition of the treatment plan and the role of the target

motion. In this setting, more information about the toxicity profile of this new approach

is compulsory before applying STAR to AF in clinical practice.

Keywords: systematic review, stereotactic arrhythmia radio ablation (STAR), atrial fibrillation, arrhythmias,

stereotactic body radiotherapy (SBRT), particle beam radiotherapy, target motion

INTRODUCTION

Atrial fibrillation (AF) is one of the most common cardiac

arrhythmias, with an estimated number 8.8 million of affected

subjects in Europe. As the prevalence of AF increases with

age, it is expected to affect approximately 18 million in the

European Union by 2060 (1) and more than 8 million people

in the United States by 2050 (2). In addition, the incidence

of AF increases in patients with cancer having an incidence

of 3.7 per 1,000 person year, also due to medical oncology

treatments (3).

Despite being benign in nature, AF represents a well-

recognized independent risk factor for stroke (4) and has been

associated with potentially severe medical conditions including

heart disease (5) and chronic kidney disease (6). Moreover, a

substantial proportion of eligible patients are undertreated with

medical therapy (7) and 74.6% of the patients (5) are symptomatic

despite ongoing medical therapy. Drugs can also have significant

side effects such as an increased risk of bleeding; all these features

determine a worsened quality of life in patients with AF (8). Based

on the presentation, duration, and spontaneous termination

of AF episodes, five types of AF can be distinguished: first

diagnosed, paroxysmal (self-terminating, in most cases within

48 h), persistent, long-standing persistent (continuous AF lasting

for1 year), and permanent AF (AF that is accepted by the

patient and physician) (9). As AF frequently originates from

an electric trigger located in the pulmonary veins, this site is

the main therapeutic target of an ablation procedure defined

as “pulmonary veins isolation” (PVI) (10). Based on further

empirical evidence, the left-posterior atrial wall has been added to

this target (11). A wide variety of approaches for PVI, including

point-by-point radiofrequency ablation or cryoballoon ablation

(9), has been described. Recently, pulsed-field ablation has been

Abbreviations: 4DCT, four-dimensional computed tomography; AF, atrial

fibrillation; BED, biological effective dose; CK, Cyberknife; CLA, conventional

linear accelerator; IMPT, intensity-modulated proton therapy; LPW, left posterior

wall; MOSFET, metal oxide semiconductor field effect transistor; MRI, magnetic

resonance imaging; MRI-Linac, MRI-linear accelerator; PBT, particle beam

therapy; PET, positron emission tomography; PRISMA, preferred reporting items

for systematic reviews and meta-analyses; PVA, pulmonary vein antra; PVI,

pulmonary vein isolation; RBE, relative biological effectiveness; RSPV-LAJ, right

superior pulmonary vein-left atrial junction; SR, sinus rhythm; STAR, stereotactic

arrhythmia radio ablation; TV, target volume; VMAT, volumetric modulated arc

therapy; VT, ventricular tachycardia; WACA, wide-area circumferential ablation;

XRT, photon radiotherapy.

introduced as an innovative technique for the ablation of AF.

It is based on the induction of cell death by the electric field

(electroporation), has shown good preliminary results in terms

of safety and efficacy (12, 13). Overall, the efficacy of these

procedures reaches 70% in patients with paroxysmal AF and

50% in those with persistent AF (14), while the percentage of

severe related complications approximates 3.5% (15). In addition,

a significant proportion of patients require more than one

procedure to achieve the permanent restoration of sinus rhythm

(SR) (16).

While

alternative

techniques

are

available,

including

ethanol,

needle,

and

bipolar

ablation,

they

are

not

without

disadvantages

or

side

effects,

including

the

uncertainty

of

properly

and

completely

damaging

the

target

(17),

cardiac

perforation

and

tamponade

(18),

or

the

inability

to

appropriately

hit

deep

and

large

substrates (19).

Other than the well-known applications in cancer, radiation

therapy has been used for the treatment of benign medical

conditions, showing both satisfactory efficacy and a good safety

profile (2022).

In the last 5 years, multiple studies have investigated the

potential of stereotactic arrhythmia radio ablation (STAR):

most of the literature is about the treatment of recurrent

ventricular tachycardia (VT) and involves both conventional

linear accelerator (CLA) (23, 24) and radiosurgery Cyberknife

R

(CK, Accuray, Sunnyvale, CA, United States) accelerator (2527).

The safety and efficacy of this new therapeutic opportunity seem

to be good in both cases. Moreover, some preclinical studies (28,

29) have used particle beam therapy (PBT) for cardiac ablation:

being able to selectively spare the most critical structures is a clear

advantage and might arguably open up to the future possibility of

re-irradiations.

An increasing body of literature has focused on intracardiac

malignancies undergoing stereotactic radiosurgery, and on

its possible related side effects (3032). Similarly, dosimetric

studies on heart irradiation have been published in the last

years (33, 34). A significant issue of cardiac radiosurgery

may be the long-term effects of radiation on myocardial,

conduction, valvular, and other cardiac tissues. These concerns

can be at least partially addressed by the study of long-

term toxicity in lymphoma (35) and centrally located lung

treatment (36).

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Stereotactic Ablation for Atrial Fibrillation

Although photons are the most known form of energy in

radiation therapy, PBT (both heavy ions and protons) are an

emerging alternative to conventional treatments. Advantages

of this form of radiotherapy are the favorable physical

characteristics and the major relative biological effectiveness

(RBE), especially when referring to carbon ion radiotherapy (37).

As a consequence, studies favoring the role of stereotactic PBT

have been developed (38) over the last couple of years.

Given the lack of comparable works, this article aims to review

the current evidence on the feasibility and efficacy of external

beam radiotherapy for AF and to provide radiation oncologists

and cardiologists with a practical overview of this theme.

MATERIALS AND METHODS

In compliance with the preferred reporting items for systematic

reviews and meta-analyses (PRISMA) (39, 40), literature research

was performed in November 2021.

Articles were researched in multiple database sources:

NCBI PubMed, EMBASE, PMID, and Scopus. The strings of

research employed and the PRISMA’s checklist are available in

Supplementary Material 1. The PRISMA flow diagram for article

selection is illustrated in Figure 1.

Both preclinical and clinical studies were considered; no data

restrictions or language limitations were applied. The inclusion of

gray literature was allowed. Studies whose focus were other forms

of arrhythmias (i.e., ventricular and nodal) were considered out

of the scope of this work and were therefore excluded.

An independent re-assessment was performed by a second

reviewer; in case of any disagreement, a third reviewer

was engaged. Selected works were independently screened

by two reviewers; whenever disagreement occurred regarding

the inclusion criteria, a third reviewer was called to resolve

the discrepancy.

Summary and definition of the radiation oncology-related

terms are available in Supplementary Material 2.

RESULTS

Following reviewing and duplicate removal, a total of 21 articles

presented from 2010 to 2021 was included in the analysis.

They consisted of one and 8 preclinical studies on treatment

plans for animals and humans treatments, respectively, 8

preclinical studies on animal models, and 4 clinical studies on

human subjects. Here follows an overview of selected articles,

categorized according to the above-mentioned criteria.

Preclinical Studies

Animals Subjects

The first study on the in vivo cardio ablation for AF was

performed in 2010 by Sharma et al. (41). Overall, preclinical

studies were conducted on healthy animals subjects, with 26

mini-pigs; in only 3 studies also canines were considered (42

44), for a total number of 27 cases (Table 1). Average or median

doses could not be calculated for preclinical works due to a lack

of information in some of the included studies.

In most cases, animals underwent general anesthesia and

received ablation in a single fraction delivered by CK. For

treatments delivered by CK, fiducials (both gold seeds and

catheter tips) were necessary to evaluate target motion. A CLA

was used in 3 cases (4446). In almost all the articles, both cardiac

and respiratory motions were considered, except for Chang

et al. (44) who acquired four-dimensional computed tomography

(4DCT) only in case of the large respiratory amplitude of the

animal, a single phase scan was considered and performed in

others. The same authors tried to use masks in 2 dogs and

had to change immobilization systems to a vacuum cushion

during simulation CT.

The target of the procedure was different across the studies:

some works evaluated either left pulmonary veins alone (41) or

the right pulmonary veins (43, 45, 46), while 3 studies considered

both targets (42, 47). Zei et al. considered only the right superior

pulmonary vein as a target because of the excessive respiratory

motion of the left superior pulmonary vein in the canine model

(43). The follow-up ranged between 1 and 6 months. Efficacy

of radiotherapy ablation was generally confirmed at doses up to

about 25–30 Gy; side effects (i.e., bronchial-mediastinal fistula

with pneumonia and sepsis) were observed in one mini-swine

1 month after irradiation when the delivered dose exceeded

37.5 Gy (46). Moreover, one animal experienced a myocardial

infection following fiducial marker placement (43) and another

pericardial effusion (44). Mild side effects were mitral valve

regurgitation after the procedure in one case (42), one mild

reduction of ejection fraction (43), and electrocardiographic, self-

limiting abnormalities on T wave after anesthesia (4 animals)

(43). On the other hand, one animal died due to pericarditis after

electrophysiological study (45). Findings in animal studies were

usually evaluated by means of electroanatomic mapping, MRI

(46), or anatomopathological study after sacrificing the subjects.

A different approach was chosen by Gardner et al. (42),

where

the

implantable

metal

oxide

semiconductor

field-

effect

transistor

(MOSFET)

dose

verification

system

and

the thermoluminescent dosimetry in pulmonary vein antra

(PVA) isolation through CK technology were compared.

The authors observed that the implantation method adopted

for the MOSFET system shows a better concordance than

thermoluminescent dosimetry since it appears not to be

affected by body fluids. However, the difference between the

measured and the predicted doses in the MOSFET system

still accounts for almost 10% when the acceptance threshold

has been set at 5% by previous studies (48, 49). The authors

hypothesized that a degree of uncertainty might derive from

the impossibility to track the dose verification system during

treatment delivery.

Dosimetric Studies

In the category of dosimetric studies, a total of 122 treatment

plans on both photon radiotherapy (XRT) and PBT were

considered, with a median dose of 25 Gy (Table 2).

A dosimetric study is a preclinical work in which subjects

undergo simulation CT without experiencing radiation treatment

or in which the treatment plan is delivered to a phantom. These

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Stereotactic Ablation for Atrial Fibrillation

FIGURE 1 | Preferred reporting items for systematic reviews and meta-analyses flow-chart.

permit the evaluation of dosimetry in the target region and organs

at risk, avoiding any toxicity.

Meanly treatment plans consisted of one single fraction and

were delivered with CK in 2 cases (50, 51). Conversely, in

the other studies, a greater dose was planned with a CLA:

50 Gy in 5 fractions (10 Gy/fraction), according to the biological

effective dose (BED) (52, 53). According to Xia et al. (52), a

radiobiological modeling study (54) was used for BED calculation

with an alpha/beta ratio of 3 Gy; in the second study, Lydiard

et al. (53) did not explain how BED was evaluated and which

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Stereotactic Ablation for Atrial Fibrillation

TABLE 1 | Main characteristics of the preclinical studies on animals included in the analysis.

Study

Energy

N subjects

Subjects

Total dose

(Gy)

N of

fractions

Target

Fiducials

Accelerator

Respiratory

motion

control

Cardiac

motion

control

Delivered

plan

Follow-up

(months)

Efficacy

Toxicity

Blanck et al. (45)

XRT

9

Mini-pigs

15–35

1

RSPV

N/A

CLA

Yes

Yes

Yes

6

Dose

32.5 Gy

No

Bode et al. (46)

XRT

8

Mini-pigs

23–40

1

RSPV

No

CLA

Yes

Yes

Yes

6

Dose

30 Gy

Dose

37.5 Gy

Chang et al. (44)

XRT

7

Canines

33

1

WACA

N/A

CLA

Partially

No

Yes

2–4

50%

Pericardial

effusion

Gardner et al. (42)

XRT

4

Canines,

mini-pigs

20–35

1

PVA

Yes

CK

Yes

Yes

Yes

5

N/A

No

Maguire et al. (47)

XRT

2

Mini-pigs

25–35

1

PVA

Yes

CK

Yes

Yes

Yes

6

Yes

Trace

MVR

Sharma et al. (41)

XRT

4

Mini-pigs

38–40

1

LPV

Yes

CK

Yes

Yes

Yes

1–6

Yes

No

Zei et al. (43)

XRT

19

Canines,

mini-pigs

15–35

1

RSPV

Yes

CK

Yes

Yes

Yes

3–6

Dose

25 Gy

Min.

reduction

EF

CLA, conventional linear accelerator; CK, Cyberknife; EF, ejection fraction; LPV, left pulmonary vein; MVR, mitral valve regurgitation; N/A, not available; PVA, pulmonary vein antra; RSPV, right superior pulmonary vein;

WACA, wide area circumferential ablation; XRT, photon radiotherapy.

TABLE 2 | Main characteristics of the dosimetric photon and particle beam-based studies included in the analysis.

Study

Energy

N

subjects

Subjects

Total

dose

(Gy)

N of

fractions

Target

Fiducials

Accelerator

Respiratory

motion

control

Cardiac

motion

control

Delivered

plan

Follow-up

(months)

Efficacy

Toxicity

Blanck et al. (50)

XRT

46

Humans

25

1

PVA

Yes

CK

Yes

Yes

No

N/A

N/A

N/A

Constantinescu et al. (58)

PBT

14

Humans

25–40

1

WACA

No

AA

Yes

Yes

No

N/A

N/A

N/A

Gardner et al. (51)

XRT

4

Humans

16–25

1

PVA ± LPW

No

CK

N/A

N/A

No

N/A

N/A

N/A

Ipsen et al. (55)

XRT

6

Humans

30

1

PVA

No

MRIL

Yes

Yes

No

N/A

N/A

N/A

Lehmann et al. (60)

PBT

3

Pigs

30–40

1

RSPV-LAJ

Yes

AA

Yes

Yes

Yes

6

Yes

No

Lydiard et al. (53)

XRT

15

Humans

50

5

PVA

No

CLA

Partially

Partially

Dynamic

phantom

N/A

N/A

N/A

Ren et al. (61)

XRT/PBT

11

Humans

25

1

WACA

No

AA/CLA

Yes

Yes

No

N/A

N/A

N/A

Richter et al. (59)

PBT

3

Pigs

30–40

1

RSPV-LAJ

Yes

AA

Yes

Yes

No

N/A

N/A

N/A

Xia et al. (52)

XRT

20

Humans

50

5

PVA

No

CLA

No

No

No

N/A

N/A

N/A

AA, adron accelerator; CLA, conventional linear accelerator; CK, Cyberknife; EF, ejection fraction; LPV, left pulmonary veins; LPW, left posterior wall; MRI, magnetic resonance imaging; MRIL, MRI-Linac, MRI-linear

accelerator; MVR, mitral valve regurgitation; N/A, not available; PBT, particle beam therapy; PVA, pulmonary vein antra; RSPV, right superior pulmonary vein; RSPV-LAJ, right superior pulmonary vein-left atrial junction;

WACA, wide area circumferential ablation; XRT, photon radiotherapy.

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Stereotactic Ablation for Atrial Fibrillation

alpha/beta ratio considered. The prescription dose was delivered

to a dynamic phantom only in the study by Lydiard et al.

(53). Specifically, the authors registered the respiratory profiles

of 3 healthy patients and subsequently associated the recorded

profiles to the phantom to deliver plans differing in complexity.

The first was created using a dynamic conformal arc and a 3 mm

target volume (TV) margin expansion, one using volumetric

modulated arc therapy (VMAT) plan, a restricted number of

monitor unit and a 3-mm TV margin expansion, the other

VMAT plans with TV margin expansions of 0, 3, and 5 mm,

respectively. All dynamic plans were compared with the static

ones, and the superiority of multileaf collimator (MLC) tracking

over tracking without MLC was demonstrated, with a minor

failure percentage appreciated through a gamma failure rate, and

a better TV dose coverage.

Only Ipsen et al. (55) involved MRI-linear accelerator (MRI-

Linac) in their work: they evaluated the role of real-time MRI

target localization and efforted the treatment planning for cardiac

radiosurgery with MRI-Linac on 6 male volunteers.

The above-described preclinical studies considered PVA as the

only target of irradiation. Only Gardner et al. (51) compared 2

different target extensions: PVA and PVA plus left posterior wall

(LPW); the last one was optimized to spare mitral valve annulus,

right coronary, and circumflex arteries. Better compliance with

radiation therapy oncology group limits was observed in the

second target set, with the purpose to reduce the dose to the

ventricles where most cardiac adverse events after radiation

therapy would originate (56).

Overall, fiducials were implanted only by Blanck et al. (50);

in this work, the authors compared a spectrum of different

tracking systems: the partially invasive one, such as a catheter

in the right atrial septum (temporary fiducials), CK marker-less

tracking system for lung tumors (XSight

R Lung, Accuray) or

ultrasound tracking (50). In the same article, Blanck et al. (50)

described a prevalidation, contouring study comprising a series

of 133 patients’ CT scans: esophagus segmentation revealed that

in 50% of the cases the organ is directly in contact with the target,

similarly to transcatheter ablation (57).

Particle Beam Therapy

Four studies focused on PBT, and carbon ions were used in all

cases: 2 works were dosimetric (58, 59) and one reported on

in vivo dosimetry on animals (60). The last one (61) compared

intensity-modulated proton therapy with XRT delivered through

VMAT and helical tomotherapy.

Constantinescu et al. (58) evaluated 9 and 5 CT scans

of complete respiratory and cardiac cycles, respectively: they

planned 25–40 Gy single fraction carbon ion treatments

involving intensity-modulated particle therapy (IMPT). Authors

defined the importance of respiratory and heartbeat motions

with a lesion displacement of, respectively,2 cm and <6 mm;

in this last case a worsening in dose coverage (V95 < 90%)

was registered. Carbon ion beam rescanning was used to

improve dose coverage.

The same rescanning technique was employed also by

Lehmann et al. (60) to reduce the interference between the

scanning motion of the beam and the target motion, the so-called

“interplay.” In their work, carbon ion irradiation in different TV

was evaluated: a 30–40 Gy single fraction treatment was delivered

on the right superior pulmonary vein-left atrial junction (RSPV-

LAJ) of 3 pigs; one of the 3 animals was irradiated with a lower

dose of 30 Gy to spare esophagus (due to specifical anatomy

of the animal), the others with 40 Gy. All the treatments were

delivered with in-beam positron emission tomography (PET) to

verify the correct deposition of carbon ions during irradiation. In

the end, they evaluated apoptotic markers employing the Western

blot technique with anti-caspase-3, antitubuline, and horseradish

peroxidase-conjugated secondary antibodies. As a result, they

found that an increase of these markers occurred 3 months

after the irradiation, but 6 months after the treatment all the

markers turned negative. With the same dataset, Richter et al. (59)

evaluated 17 treatment plans (3 on RSPV-LA, 14 on other targets)

with ECG-based-4D-dose reconstruction, showing higher safety

with respect to cardiac structures and efficient dose verification.

The most recent article included on PBT, Ren et al. (61),

evaluated dosimetric properties of intensity-modulated proton

therapy in comparison with VMAT and tomotherapy treatment

planning; the prescription dose was 25 Gy in all plans. The

proton-based technique resulted in a significantly reduce dose

in surrounding tissues, compared to photon-based ones, in

patients with AF.

Clinical Studies

Three of the selected studies considered human subjects, with

a total number of 6 patients (Table 3). The first clinical

work is a case report by Monroy et al. (62) on a 59-year-

old man with symptomatic AF suffering from adverse effects

caused by antiarrhythmic drugs and an ischemic stroke in

oral anticoagulant therapy. The need of performing catheter

manipulation within the left atrium, which is required by

classical PVI, was judged as a contraindication to a catheter-

based procedure. Therefore, a radio ablation was proposed

by the cardiologist, and the patient underwent radiosurgery,

delivered by CK in a single fraction, with a prescription dose

to pulmonary veins of 25 Gy to the 71% isodose line. Details

on the use of fiducials were not reported, and the details of

cardiac motion control. Respiratory motion was compensated by

synchrony image guidance during the whole course of treatment

delivery. Six months after the procedure the patient developed

a permanent AF requiring him to restart the medical therapy.

An MRI was performed 1 year the after procedure and a late

enhancement was recorded at the radio-ablated structure, which

may correspond to the development of a scar.

A second study [Qian et al. (63)] involved 2 patients with

symptomatic AF who had refused a catheter procedure and

had agreed to an experimental non-invasive ablation. Both had

undergone a fiducial placement and a subsequent simulation

contrast-enhanced CT scan. A prescription dose of 25 Gy was

delivered through a CK accelerator in both cases. Patients were

followed for 24 months (patient 1) and 48 months (patient

2), showing the absence of any significant treatment-related

side effects. Six months after irradiation, patient 1 developed

persistent AF, leading to permanent medical therapy. Conversely,

the second patient had no AF recurrences during the entire

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TABLE 3 | Main characteristics of the clinical studies included in the analysis.

Study

Energy

N

subjects

Total dose

(Gy)

N of

fractions

Target

Fiducials

Accelerator

Respiratory

motion

control

Cardiac

motion

control

Delivered

plan

Follow-up

(months)

Efficacy

Toxicity

Monroy et al. (62)

XRT

1

25

1

PVA

N/A

CK

Yes

N/A

Yes

12

No

No

Qian et al. (63)

XRT

2

25–35

1

WACA

Yes

CK

Yes

Yes

Yes

48

50%

No

Shoji et al. (64)

XRT

3

22–30

1

WACA

Yes

CK

Yes

Yes

Yes

24

No

No

CK, Cyberknife; LPV, left pulmonary veins; N/A, not available; PVA, pulmonary vein antra; WACA, wide area circumferential ablation; XRT, photon radiotherapy.

follow-up. Only the second patient performed a pre- and post-

ablation MRI, showing evidence of a scar at the radiosurgery

site after 1 year.

The most recent article in the clinical area has been published

by Shoji et al. (64): 3 oncologic patients with refractory AF

were treated with a target dose of 25–30 Gy in a single fraction

delivered by CK. The TV was represented by a “box” lesion

set including a circumferential wide-area ablation (WACA) set

around pulmonary veins and the maximum follow-up was

24 months. One patient died 4 days after the procedure due to

oncologic disease. The autopsy revealed evidence of fibroblasts

and fibrogenesis in the region of radio-ablated tissues. On the

other two patients, who remained in AF, clear evidence of clinical

efficacy cannot be found: authors encountered some limitations

as a consequence of the second patient’s refusal to undergo

electrograms of LPW recorded from the esophagus. However,

the third patient underwent this exam and no atrial potentials

were seen from the esophageal electrogram recordings after radio

ablation. This evidence suggests an electrical block, which is

the clinical goal of the procedure. No acute or late effects were

registered during follow-up.

Gray Literature

Two of all the articles selected were gray literature: the first was

the preclinical study of Rahimian et al. (65) which included 3

patients’ treatment plans for a 25 Gy single fraction therapy.

The most recent study, Gregucci et al. (66) is currently enrolling

patients, and results are not yet available. All the studies

considered PVA as TV. No information about efficacy or toxicity

is now available from all this literature but it suggests the

increasing interest in this particular topic.

DISCUSSION

Main Evidence

Results from our work show the application of STAR for AF.

A prescription dose of at least 25 Gy in a single fraction

is necessary to have good efficacy despite an acceptable

toxicity profile.

The major cause of failure of traditional catheter ablation of

AF is incomplete circumferential vein isolation (9). It is worth

considering that, according to the existing literature on catheter

ablation, the choice of the target (11) and the circumferential scar

(67) is essential to obtain an effective procedure. Target selection

appears to have the same importance in non-invasive cardio-

ablation procedures, as confirmed by target heterogeneity among

considered studies (see section “Results”).

Target motion control, involving fiducials or other simulation

strategies (4DCT and cardio-CT or electroanatomic mapping) is

deemed necessary to improve the accuracy of the procedure.

It is worth saying that, despite the interest in the topic, a

limited number of humans has currently undergone STAR for AF

and only 2 articles including more than one patient have been

published (63, 64). In the study of Quian et al. (63), efficacy was

observed in one of 2 treated patients, but no detail on treatment

plan features was provided by the authors; moreover, 2 different

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Stereotactic Ablation for Atrial Fibrillation

pathways of preprocedural and follow-up exams were applied,

which cannot be considered as being completely comparable.

The absence of toxicity was the only shared feature between the

patients included. In the study of Shoji et al. (64), no acute or late

effects were observed; nevertheless, the choice to select oncologic

patients makes it more difficult to evaluate the endpoint of

efficacy. Even if clinical efficacy on human subjects is difficult

to be defined in a limited sample, fibrosis (63, 64), or electrical

block (64) was observed in the radio-ablated area in both studies.

A similar finding, obtained by an MRI exam, was recorded in

the case report (62). All the above-mentioned evidence may be

interpreted as the confirmation of the radio-ablation lesion.

In

conclusion,

available

evidence

reports

acceptable

tolerability

of

the

cardio-ablation

treatment

on

humans;

further analyses, together with the newest results coming from

the current “gray literature,” however, are deemed necessary to

reach the highest level of efficacy.

Validation of Stereotactic Arrhythmia

Radio Ablation With Regard to Different

Experimental Settings

We observed a prevalence of preclinical studies, the majority of

which involved mini pigs. This choice can be explained by their

relative growth stability and the consequent capability of weight

maintenance during follow-up. Three of the analyzed studies also

considered a canine model (4244). However, regardless of the

chosen animal models (68), transferability concerns for clinical

applications in humans exist. Significant examples may be the

incomplete pericardium of dogs (47) or the different cardiac

chambers anatomy and number of pulmonary veins in humans

and canines (44). Specifically, these anatomical peculiarities could

affect respiratory and cardiac target motions, which are essential

parameters in treatment planning.

When evaluating the preclinical studies on animals it has been

shown that the efficacy is higher when mini pigs (41, 47) are

treated as compared with canines (44) or mixed samples (42).

Total prescription doses in the considered works ranged from

15 to 50 Gy/fraction and the minimum dose threshold for

efficacy was 25 Gy. Most of the studies encompassed stereotactic

radiosurgery delivered in a single fraction except for few articles

describing 5-fraction treatments with a dose of 10 Gy/fraction

(total dose: 50 Gy). This comparability is based on the BED which

was calculated by the authors (52) using a radiobiological model

to avoid the overestimation of the total dose resulting from the

linear-quadratic BED calculation when the dose is greater than

8–10 Gy (69). Of note, even if BEDs were considered comparable,

the heart tissue is a late responder and its alpha/beta ratio is about

3 Gy (31, 52) with the consequence that the effect may be superior

with higher doses delivered in a single fraction than with lower

fractionated doses.

A discrete number of studies based on the treatment plan

evaluation or delivery of the treatment on a dynamic phantom

can be found in the literature: even if they appear to be more

acceptable from the ethical standpoint, someone may question

if the evidence acquired from these studies are comparable, in

terms of efficacy and safety, with those acquired from the clinical

setting; in some cases (53), authors started from a study of

cardiac and respiratory montions on healthy patients, raising the

question whether the respiratory and cardiac motions are really

comparable in healthy patients with AF, as discussed below.

Role of the Target Motion

The role of the target motion was furthermore discussed in

almost all studies. This topic gains importance since the natural

motion of the organs influences not only the myocardial or the

conduction tissue around the target but also the other organs at

risk, the most important one appearing to be the esophagus. The

problem of organ motion was solved by some authors (50, 59, 60)

by adopting different fiducials such as seeds or catheters, whereas

other ones did not (46, 5153). The presence of fiducials makes

the tracking useful in the positioning of the patient and in the

reduction of the margin of error due to cardiac and respiratory

motion, but it implies the use of tools that are against the peculiar

nature of the procedure in terms of non-invasiveness.

Grimm et al. (70) and Abelson et al. (71) faced the problem

of organs at risk doses by reviewing literature and patients’ data,

respectively, and elaborated dosimetric tables as references for the

colleagues’ work.

In the end, it is important to remember how it is possible

that a dilated heart with AF appears to have less movement than

a healthy one (61, 72): so, it is also possible that all dosimetric

studies on healthy subjects are not completely suitable for the

patients with real-AF and more investigations could be necessary.

At last, it is worth noticing the interesting application of MRI

to approach the problem of target motion (55, 73): on the one

hand, by quantifying target motion ranges on MRI, on the other

hand by analyzing the dosimetric benefits of margin reduction

assuming the application of real-time motion compensation.

Supporting this hypothesis, a recent article by Lydiard

et al. (74), not included in the selection, investigated the

feasibility of non-invasive MRI-guided tracking of cardiac-

induced target motion in AF cardiac radio ablation by comparing

a direct tracking method and 2 indirect tracking methods

(tracking indirect left atrial or other targets). They suggested

the applicability of non-invasive MRI-guided tracking, showing

a potential improvement in treatment efficacy.

Particle Beam Therapy: Pros and

Prospectives

Both XRT and PBT involve ionizing radiations, but the second

one can deliver its maximum dose at a specific depth (Bragg peak,

Figure 2) to the TV while no dose in the surrounding tissues (75).

Carbon ion should be particularly indicated for the aim of

cardio ablation because of the favorable RBE (three times as much

as the photons’ one) and the possibility of smaller beam foci and

less lateral scattering.

In the included articles, pencil beams were used to better

modulate the beam on the TV; the limit of these thin rays is a

major sensibility to motion and setup errors, then the correct

position of the beam’s distal edge remains unknown (75). Ren

et al. (61) decided to study this phenomenon in their work using

a cardiac motion scan from a patient case. Nevertheless, beam

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Franzetti et al.

Stereotactic Ablation for Atrial Fibrillation

FIGURE 2 | Bragg peak in PBT. Reprinted from Mustapha et al. (81) with the

permission of AIP Publishing.

rescanning and 4D dose calculation (58) or the use of in-beam

PET can reduce the problem (60).

An interesting biological hypothesis about the effectiveness

of carbon ions in arrhythmia ablation was formulated by

Amino et al. (76): they studied the role of the upregulation of

connexin-43, a protein expressed during myocardial remodeling

in myocardial infarction or cardiac hypertrophy. This remodeling

effect on gap junctions may reduce the conduction of the

arrhythmia through myocardial tissue.

Although photons and carbon ions are so different, according

to the articles selected, the time to detect a scar in an

anatomopathological analysis is similar and it spans from weeks

to months. As further evidence, the process of fibrosis and scar

creation starts after the activation of the apoptotic cascade (77,

78), according to Lehmann et al.’s results (60).

Use of Stereotactic Arrhythmia Radio

Ablation in Atrial Fibrillation Versus

Ventricular Tachycardia

During the evaluation of the efficacy and safety of STAR in

AF, some considerations about the comparison between AF and

VT are necessary. First, it is worth underlying that specific

peculiarities characterize the anatomical and structural substrate

for AF as for VT, which reflect in different treatment approaches

and need to safeguard surrounding healthy structures. For

these reasons, some assumptions that have been preliminarily

validated in the field of VT may not be true for AF. Ventricular

arrhythmias, that may deserve STAR, are usually life-threatening;

patients present with recurrent and/or refractory VTs and are

not eligible for conventional approaches or these have proven

ineffective. In this clinical setting, STAR represents a promising

option, thus more risks, even unknown ones, are allowed. To

the best of our knowledge, in literature few severe adverse

events, definitely correlated to STAR, are reported. In particular,

one patient died of esophagopericardial fistula after 9 months

from STAR: of note, the patient had previous bypass surgery

with a gastroepiploic artery that might have contributed to this

severe adverse event (79); few clinically relevant or symptomatic

radiation-induced pericarditis and pericardial effusion and a

gastropericardial fistula 2 years after STAR were recorded (80).

Being AF a benign arrhythmia, more attention to the safety

rather than the efficacy of STAR is mandatory.

In this setting, more information about the toxicity profile of

this new approach is compulsory before applying STAR to AF

in clinical practice; this is also the reason why not many clinical

articles are available in the literature so far.

Strengths and Limitations

All the above-mentioned works and other already published

reviews discuss every type of tachydysrhythmias without a

specific focus on AF. The strength of this review is the specificity

of the topic treated: stereotactic radio ablation of AF through both

XRT and PBT. In this regard, we would like to underline once

again that these considerations do not necessarily apply to other

patients’ conditions (e.g., non-oncological patients).

The main limitations of this work are the relative paucity of

works, which is in line with the novelty of the field, and the low

evidence of available literature. Moreover, given the nature of

our work (qualitative rather than quantitative synthesis), and the

relative paucity of studies, it was not possible to fully estimate

publication bias—if any—through a funnel plot. To at least

account for such potential weakness, gray literature was also

included. As a matter of fact, while these works are not peer-

reviewed, good-quality gray literature is a source of up-to-date

information on ongoing clinical efforts.

CONCLUSION

Stereotactic

radio

ablation

is

an

innovative

non-invasive

procedure already in use for ventricular cardiac arrhythmias.

Radio ablation of AF, with a prescription dose at least of 25 Gy,

might be considered among the future therapeutic option for

AF, especially when an interventional ablation procedure is

contraindicated or proved ineffective.

Carbon ions are a highly promising radiation technique due to

their TV coverage and, at the same time, their greater capability

to spare organs at risk; this may be a strong point to achieve an

effective safer alternative application for the heart.

Essential issues, such as:

– duration of AF before treatment,

– target definition and motion, and

– doses delivered to the target and organs at risk,

deserve further evaluation to define proper indications and

modalities to benefit the most from the use of STAR in

patients with AF.

DATA AVAILABILITY STATEMENT

The original contributions presented in the study are included

in the article/Supplementary Material, further inquiries can be

directed to the corresponding author.

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May 2022 | Volume 9 | Article 849201

Franzetti et al.

Stereotactic Ablation for Atrial Fibrillation

AUTHOR CONTRIBUTIONS

JF contributed to conception of the study and wrote the first draft

of the manuscript. SV wrote the first draft of the manuscript

and was the third reviewer of the literature. VC performed the

literature research and contributed to write the first draft of the

manuscript. CP was the first reviewer of the literature. EC, GP,

and FC contributed to write sections of the manuscript. MP

designed and prepared the tables. AMC was the second reviewer

of the literature. DA and CT critically revised the final version.

BAJ-F contributed to conception of the study and critically

revised the final version. CC designed the study and contributed

to wrote the first draft of the manuscript and the final revision. All

authors contributed to manuscript revision, read, and approved

the submitted version.

FUNDING

SV was partially supported by the Italian Ministry of Health

with Progetto di Eccellenza. SV was a Ph.D. student at the

European School of Molecular Medicine (SEMM), Milan. CP

was supported by a research grant from the Fondazione IEO-

CCM entitled “STereotactic Radio Ablation by Multimodal

Imaging for Ventricular Tachycardia (STRA-MI-VT)” and by

a research grant from the AIRC entitled “Phase I/II clinical

trial on single fraction ablative preoperative radiation treatment

for early-stage breast cancer.” The institutions IEO IRCCS and

CCM IRCCS are partially supported by the Italian Ministry

of Health with 5 × 1,000 funds and Ricerca Corrente (RC

2019—EF 5A—ID2754331 to Centro Cardiologico Monzino

IRCCS). The sponsors did not play any role in the study design,

collection, analysis, and interpretation of data, in the writing of

the manuscript, or in the decision to submit the manuscript for

publication.

SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found

online

at:

https://www.frontiersin.org/articles/10.3389/fcvm.

2022.849201/full#supplementary-material

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